Expression of Components of the Renin-Angiotensin System in Pyogenic Granuloma

Papali'i-Curtin, Jessica C; Brasch, Helen D.; Schaijik, Bede van; Jongh, Jennifer de; Marsh, Reginald; Tan, Swee T.; Itinteang, Tinte

doi:10.3389/fsurg.2019.00013

Cited by 12 publications

(12 citation statements)

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“…Further studies with a larger sample size including functional experiments are required to confirm our findings. Components of the renin–angiotensin system (RAS) have been shown to be expressed by similar populations in infantile hemangioma ( 41 ), pyogenic granuloma ( 42 ), and venous malformation ( 43 , 44 ). Investigation into the expression of RAS on a primitive population in extracranial AVM may lead to novel targeting of the population using available medications.…”

Section: Discussionmentioning

confidence: 99%

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

et al. 2021

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Objectives: Arteriovenous malformation (AVM) consists of a nidus with poorly formed low-resistance vessels in place of a functional capillary network. The role of somatic mutations in embryonic stem cells (ESCs) and vascular anomalies and the presence of primitive populations in vascular anomalies led us to investigate the presence of a primitive population in extracranial AVM.Methods: Extracranial AVM tissue samples from 12 patients were stained for stemness-associated markers OCT4, SOX2, NANOG, KLF4, and c-MYC using immunohistochemical staining. In situ hybridization (ISH) was performed on six tissue samples to determine transcript expression. Western blotting and RT-qPCR were performed on two AVM-derived primary cell lines to determine protein and transcript expression of these markers, respectively. Immunofluorescence staining was performed on two tissue samples to investigate marker co-localization.Results: Immunohistochemical staining demonstrated the expression of OCT4, SOX2, KLF4, and c-MYC on the endothelium and media of lesional vessels and cells within the stroma of the nidus in all 12 AVM tissue samples. ISH and RT-qPCR confirmed transcript expression of all five markers. Western blotting showed protein expression of all markers except NANOG. Immunofluorescence staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ population within the endothelium and media of the lesional vessels and cells within the stroma of the AVM nidus.Conclusions: Our findings may suggest the presence of a primitive population within the AVM nidus. Further investigation may lead to novel therapeutic targeting of this population.

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Section: Discussionmentioning

confidence: 99%

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

et al. 2021

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“…The primitive subpopulation on the endothelium expresses the ESC markers OCT4, SOX2, NANOG, and pSTAT3, whereas a subpopulation within the interstitium expresses SOX2, NANOG, and pSTAT3 ( 51 ). These subpopulations in PG also express components of the RAS ( 52 ). The expression of ACE on the endothelium of the microvessels suggests paracrine conversion of ATI to ATII, which may impact cellular proliferation and angiogenesis within PG ( 54 , 103 ).…”

Section: Vascular Tumorsmentioning

confidence: 99%

“…The expression of ACE on the endothelium of the microvessels suggests paracrine conversion of ATI to ATII, which may impact cellular proliferation and angiogenesis within PG ( 54 , 103 ). It has been proposed that the presence of AT 1 R on the microvessels within PG may contribute to immature microvessel formation by influencing the ESC-like population to differentiate down an endothelial phenotype ( 52 , 104 ). If cells expressing stemness-associated markers preferentially differentiate toward an endothelial phenotype under the influence of the RAS, this could be targeted by RAS modulators ( 52 ).…”

Section: Vascular Tumorsmentioning

confidence: 99%

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Cell Populations Expressing Stemness-Associated Markers in Vascular Anomalies

et al. 2021

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Treatment of vascular anomalies (VAs) is mostly empirical and, in many instances unsatisfactory, as the pathogeneses of these heterogeneous conditions remain largely unknown. There is emerging evidence of the presence of cell populations expressing stemness-associated markers within many types of vascular tumors and vascular malformations. The presence of these populations in VAs is supported, in part, by the observed clinical effect of the mTOR inhibitor, sirolimus, that regulates differentiation of embryonic stem cells (ESCs). The discovery of the central role of the renin-angiotensin system (RAS) in regulating stem cells in infantile hemangioma (IH) provides a plausible explanation for its spontaneous and accelerated involution induced by β-blockers and ACE inhibitors. Recent work on targeting IH stem cells by inhibiting the transcription factor SOX18 using the stereoisomer R(+) propranolol, independent of β-adrenergic blockade, opens up exciting opportunities for novel treatment of IH without the β-adrenergic blockade-related side effects. Gene mutations have been identified in several VAs, involving mainly the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways. Existing cancer therapies that target these pathways engenders the exciting possibility of repurposing these agents for challenging VAs, with early results demonstrating clinical efficacy. However, there are several shortcomings with this approach, including the treatment cost, side effects, emergence of treatment resistance and unknown long-term effects in young patients. The presence of populations expressing stemness-associated markers, including transcription factors involved in the generation of induced pluripotent stem cells (iPSCs), in different types of VAs, suggests the possible role of stem cell pathways in their pathogenesis. Components of the RAS are expressed by cell populations expressing stemness-associated markers in different types of VAs. The gene mutations affecting the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways interact with different components of the RAS, which may influence cell populations expressing stemness-associated markers within VAs. The potential of targeting these populations by manipulating the RAS using repurposed, low-cost and commonly available oral medications, warrants further investigation. This review presents the accumulating evidence demonstrating the presence of stemness-associated markers in VAs, their expression of the RAS, and their interaction with gene mutations affecting the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways, in the pathogenesis of VAs.

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“…This has been shown to be the case in numerous cancer types, including glioblastoma (136–138), metastases to the liver from colon adenocarcinoma (139, 140), head and neck cutaneous squamous cell carcinoma (141), and oral cavity squamous cell carcinoma affecting the buccal mucosa (142, 143), oral tongue (144–146), and lip (147, 148). In addition, components of the RAS have also been demonstrated on the tumor stem cells of benign tumors such as meningioma (149, 150), infantile hemangioma (151, 152), and pyogenic granuloma (153). Importantly, the expression of cathepsins B, D, and G in some of these cancer types (74, 138, 140, 146, 150) suggests the presence of bypass loops of the RAS which could circumvent the action of traditional RAS inhibitors and offer a potential explanation for the differing findings of cancer risk and cancer survival with long-term use of traditional RAS inhibitors.…”

Section: Cancer Stem Cells Express Components Of the Rasmentioning

confidence: 99%

Therapeutic Targeting of Cancer Stem Cells via Modulation of the Renin-Angiotensin System

Roth

Wickremesekera

et al. 2019

Front. Oncol.

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Cancer stem cells (CSCs) are proposed to be the cells that initiate tumorigenesis and maintain tumor development due to their self-renewal and multipotency properties. CSCs have been identified in many cancer types and are thought to be responsible for treatment resistance, metastasis, and recurrence. As such, targeting CSCs specifically should result in durable cancer treatment. One potential option for targeting CSCs is by manipulation of the renin-angiotensin system (RAS) and pathways that converge on the RAS with numerous inexpensive medications currently in common clinical use. In addition to its crucial role in cardiovascular and body fluid homeostasis, the RAS is vital for stem cell maintenance and differentiation and plays a role in tumorigenesis and cancer prevention, suggesting that these roles may converge and result in modulation of CSC function by the RAS. In support of this, components of the RAS have been shown to be expressed in many cancer types and have been more recently localized to the CSCs in some tumors. Given these roles of the RAS in tumor development, clinical trials using RAS inhibitors either singly or in combination with other therapies are underway in different cancer types. This review outlines the roles of the RAS, with respect to CSCs, and suggests that the presence of components of the RAS in CSCs could offer an avenue for therapeutic targeting using RAS modulators. Due to the nature of the RAS and its crosstalk with numerous other signaling pathways, a systems approach using traditional RAS inhibitors in combination with inhibitors of bypass loops of the RAS and other signaling pathways that converge on the RAS may offer a novel therapeutic approach to cancer treatment.

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Expression of Components of the Renin-Angiotensin System in Pyogenic Granuloma

Cited by 12 publications

References 37 publications

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

Cell Populations Expressing Stemness-Associated Markers in Vascular Anomalies

Therapeutic Targeting of Cancer Stem Cells via Modulation of the Renin-Angiotensin System

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